2-47806751-CTTTTTTTTTTTTTTT-CTTTT

Variant names:

• chr2-47806751-CTTTTTTTTTTT-C
• rs59056100
• NM_000179.3:c.4002-20_4002-10delTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000179.3(MSH6):​c.4002-20_4002-10delTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,646 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 0)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36
• Publications: 0 publications found

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.4002-20_4002-10delTTTTTTTTTTT		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4098-20_4098-10delTTTTTTTTTTT		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.4008-20_4008-10delTTTTTTTTTTT		intron	N/A	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.4002-20_4002-10delTTTTTTTTTTT		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3349-20_*3349-10delTTTTTTTTTTT		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.4029-20_4029-10delTTTTTTTTTTT		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.00000723 AC: 1 AN: 138394 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000157

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.66e-7 AC: 1 AN: 1306252 Hom.: 0 AF XY: 0.00000153 AC XY: 1 AN XY: 652182

African (AFR) AF: 0.00 AC: 0 AN: 28098

American (AMR) AF: 0.00 AC: 0 AN: 36428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24240

East Asian (EAS) AF: 0.00 AC: 0 AN: 34568

South Asian (SAS) AF: 0.00 AC: 0 AN: 75958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5178

European-Non Finnish (NFE) AF: 9.95e-7 AC: 1 AN: 1004658

Other (OTH) AF: 0.00 AC: 0 AN: 54250

GnomAD4 genome AF: 0.00000723 AC: 1 AN: 138394 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66768

African (AFR) AF: 0.00 AC: 0 AN: 37976

American (AMR) AF: 0.00 AC: 0 AN: 13576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4420

South Asian (SAS) AF: 0.00 AC: 0 AN: 4248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000157 AC: 1 AN: 63842

Other (OTH) AF: 0.00 AC: 0 AN: 1886

Alfa AF: 0.00 Hom.: 174

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs59056100; hg19: chr2-48033890;